Gastroenterology Hepatology

Hepatotoxicity

How can I be sure that the patient has drug-induced liver injury?

Description of the problem

Hepatotoxicity, a term used to describe liver injury with possible hepatic dysfunction, is a broad term. In the context of this chapter, we will focus on nonacetaminophen drug-induced hepatotoxicity or idiosyncratic drug-induced liver injury (DILI). Although relatively rare in relation to various chronic liver diseases such as viral hepatitis, alcoholic and nonalcoholic fatty liver disease, and metabolic liver diseases such as hemochromatosis, DILI is important to recognize. It is thought that DILI occurs in the range of 1 in 10,000 to 1 in 100,000 cases, but under-reporting and lack of clear diagnostic criteria and appropriate follow-up limit the accuracy of the true prevalence of DILI. It is important to recognize DILI early because identification of the problem and stopping the offending drug is critical to resolution of the hepatic injury. In fact, data suggest that once jaundice appears, mortality approaches 10%.

A tabular or chart listing of features and signs and symptoms

What are the presenting clinical characteristics of drug-induced liver injury?

DILI can occur at any age, but the majority of reported cases occur between the ages of 18 to 65. Typically, a single drug is implicated (>70%). Herbal or dietary supplements are becoming increasingly more common as a cause for DILI, accounting for 9% of all cases.

Clinical presentations vary considerably from asymptomatic elevations in liver enzymes to deeply jaundiced with acute liver failure. As mentioned previously, jaundice is associated with a 10% risk for mortality. Liver enzyme elevations can be categorized into three different patterns:

1. Hepatocellular: 57-58%

2. Mixed hepatocellular/cholestatic: 20-22%

3. Cholestatic: 20-23%

More than 1100 compounds ingested by humans have been linked to DILI. The most common drugs that have been implicated in DILI include:

  • Antimicrobials: 45%

In two large prospective clinical studies, augmentin (amoxicillin-clavulanate), nitrofurantoin, isoniazid, and TMP/SMZ were the most common.

  • Central nervous system agents: 15%

  • Immunomodulatory agents: 5%

  • Analgesics/NSAIDS: 5%

  • Antihypertensive agents: 5%

  • Antineoplastic agents: 5%

  • Lipid-lowering agents: 3%

  • Herbal supplements, especially those taken for weight loss or muscle building seem to be increasing in frequency as their use rises in the general population. Hydroxycut, green tea, and black cohosh have all been associated with reported cases of DILI.

The length of time from ingestion of the drug to onset of symptoms, the latency period, is quite variable but generally is 1 week to 3 months.

Up to one-third of patients may present with immunoallergic symptoms consisting of fever, rash, and eosinophilia and this typically occurs in the first few weeks of drug exposure.

Exposure to greater than 50 mg/day of a particular agent increases the risk of developing DILI. Two studies have demonstrated that 77 to 80% of all DILI cases occurred in patients taking more than 50 mg/day of the medication. Additionally, it appears that drugs with higher than 50% hepatic metabolism are associated with an increased risk for DILI.

Up to 10% of patients with drug-induced liver injury will meet diagnostic criteria for acute liver failure with concomitant coagulopathy and altered mental status.In those patients who evolve to acute liver failure, prognosis is poor with a mortality of over 40% and liver transplantation requirements in 40%.

How can I confirm the diagnosis?

There is no "gold standard" for diagnosing DILI. It requires a high index of suspicion and is based on a very good clinical history, in which detailed drug ingestion questions are asked and other well-defined etiologies of liver injury are excluded. Care should be given to assess for a temporal association between ingestion of a drug and the onset of symptoms. It is also very helpful to look back and see if a prior set of baseline liver enzymes can be obtained. The typical interval from exposure to onset of hepatotoxicity is 1 week to 3 months, generally. Some notable exceptions are outlined above.

The Roussal Uclaf Causality Assessment Model (RUCAM) is an algorithm that has been proposed to help define causality for a drug. It is quite complicated and the reliability of this algorithm has been questioned. Therefore, RUCAM, although utilized in research, is typically not utilized in clinical practice.

LiverTox (http://www.livertox.nih.gov/) is a free online resource supported by the National Library of Medicine and National Institute of Diabetes and Digestive and Kidney Diseases to provide detailed information on over 600 medications (including prescription and non-prescription medications, herbal remedies, and dietary supplements) and their reported hepatotoxicities.

As part of the assessment for drug-induced liver injury, the R ratio is calculated with the formula:(ALT value/ALT ULN) / (Alk P value/Alk P normal).This value is suggestive of the pattern of liver presentation wherein a value >5 is defined as hepatocellular, <2 is defined as cholestatic, and those in between are considered a mixed pattern.

What other diseases, conditions, or complications should I look for in patients with drug-induced injury?

What are the risk factors for the patient with drug-induced liver injury?

Major risk factors

Children and the elderly appear to be at increased risk for specific drugs. Children are at increased risk for DILI with valproic acid and, when taking aspirin, Reye's syndrome. The elderly often take multiple medications and this may be associated with an increased risk for DILI. The pattern of liver injury may be different as well, as data suggest older patients are more likely to present with a cholestatic or mixed pattern to their liver enzyme elevations.

Whether female gender is a risk factor in and of itself is controversial. Although earlier studies suggested that women were at higher risk, several more recent studies suggest that there is no gender difference with regard to DILI occurrence. However, data suggest that younger females are more likely to present with a hepatocellular pattern to the liver enzyme elevations and that women are more likely to progress to acute liver failure.

Patients with underlying chronic hepatitis B or C may be at increased risk for DILI, especially with intake of some medications, such as antituberculosis agents. Coinfection with hepatitis B or C in the setting of HIV, may predispose patients to DILI. In contrast, patients with nonalcoholic fatty liver disease (NAFLD) do not appear to be at increased risk for DILI, including statins.

Diabetes appears to also place patients at increased risk for DILI. Data from the Drug-Induced Liver Injury Network (DILIN) show that diabetic patients have a more than 2-fold increased risk of DILI.

Genetic associations

Potential genetic risk factors appear to exist for some patients presenting with idiopathic DILI. The genetic variability of the human leukocyte antigen (HLA) system has recently been recognized as the most important risk factor for DILI. Genomewide association studies (GWAS) has shown that the HLA-B*5701 genotype (rs2395029[G]) in flucloxacillin-associated DILI is associated with an odds ratio of 80.6 (95% CI:22.8-284.9) for DILI. On a clinical level, despite this high odds ratio, given the rarity of flucloxacillin with DILI, this translates into an absolute risk of 1 in 500-1000 of developing DILI if this mutation is identified.

Other GWAS have found an HLA variant associated with ximelagatran. These two studies have paved the way for future pharmacogenetic studies.

What is the right therapy for the patient with drug-induced liver injury?

Management of patients with suspected DILI

Exclude other etiologies for liver enzyme elevations. If the patient is presenting with a hepatocellular pattern to the liver enzyme elevations, then obtain viral serologies for hepatitis A, B, and C and, in some cases, measuring the viral load directly is advocated.

Recent data suggest that hepatitis E may also be the culprit, and consideration also should be given to testing for this viral infection. Thought should also be given to autoimmune hepatitis because it can mimic DILI.

If presenting with a mixed or cholestatic pattern, then hepatic imaging should also be considered. It is routine to start with an abdominal ultrasound, but in some cases, obtaining an MRI with good views of the biliary system are warranted.

Once a thorough drug history is obtained and a suspected agent is identified, the latter should be immediately discontinued.

Performing a liver biopsy is not always necessary.However, it should be considered if autoimmune hepatitis remains in the differential after workup.Other cases in which to consider liver biopsy include patients who discontinue the offending agent but continue to have increase in liver biochemical tests or worsening liver function, failure of ALT or AP to decrease by 50% or more after 1-2 months, or persistent liver biochemical test abnormalities after 6 months.If there are clinical reasons to attempt re-exposure to the suspected agent, then liver biopsy is also recommended.

Once the offending agent is stopped and the diagnosis has been made, good supportive care is critical. In addition to this, consideration should be given to the use of intravenous N-acetylcysteine (NAC). Data from a recent double-blind study showed that a 72-hour infusion of NAC improved transplant-free survival, albeit overall survival at 3 weeks was not improved. Patients benefiting the most from the NAC infusion were those presenting early in the course of their illness with grade I to II coma. The use of steroids or ursodeoxycholic acid cannot be advocated, given the paucity of positive clinical data supporting its use.

What is the most effective initial therapy?

Stop the offending agent.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

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A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

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Listing of these, including any guidelines for monitoring side effects.

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How should I monitor the patient with drug-induced liver injury?

Long-term concerns

The majority of patients who experience DILI will have a complete recovery. However, chronic liver disease may develop in 6% to 14% of DILI patients. In a recent prospective study, 6 months after development of DILI, liver enzymes remained elevated in 14% of cases. This does not appear to translate into untoward clinical outcomes, although, as a 10 year follow-up study from Sweden demonstrated, the development of clinical significant liver disease was less than 4%.

Some medications have been linked to the development of DILI and autoimmune liver disease. This is typically characterized by the occurrence of high-titer autoantibodies. Medications linked to this development include:

1. Hydralazine

2. Diclofenac

3. Nitrofurantoin

4. Minocycline

Progression to acute liver failure

Acute liver failure (ALF) due to idiosyncratic DILI should be differentiated from acetaminophen-induced ALF in that patients presenting with idiosyncratic DILI present with only modest elevations in the serum aminotransferases. Almost all other forms of ALF, including acetaminophen-induced, will present with significantly higher elevations in the serum aminotransferases.

It has been estimated that about one-quarter of patients with idiosyncratic DILI ALF will present with the immunoallergic reaction characterized early by rash, fever, eosinophilia, or autoantibody positivity. A large, multicenter, prospective US clinical registry of ALF recently showed that 11% of reported cases of ALF were due to idiosyncratic DILI. The antimicrobial class of drugs (46%) was the most likely culprit for DILI ALF, with isoniazid, nitrofurantoin, and TMP-SMZ being the 3 most common. Seventy percent of cases were female. Transplant-free survival was 27% and was predicted based on the degree of hepatic dysfunction, typically assessed by level of coma, bilirubin elevation, and coagulopathy.

Statin-induced hepatotoxicity

Statins are one of the most frequently prescribed medications in the world and clinical trials have shown them to be very safe, with fewer than 3% of patients developing elevations in serum aminotransferases to more than 3 times the upper limit of normal. To date, a total of 113 cases of DILI attributable to statins have been described in the literature. Utilizing the United States DILI Network and the Spanish Registry, it appears that statins account for about 3% of all reported DILI cases.

Although most patients recovered from their illness, some cases progress to ALF and death or need for liver transplantation. In the largest series reported to date on 73 statin-related DILI cases from Sweden, there were 2 deaths and 1 liver transplant. In addition, data from the ALF Study Group demonstrates that statins were implicated as the cause of ALF in 6 cases (4.5%). Likely as a result of their more frequent use, atorvastatin and simvastatin have been implicated as the most common statins associated with DILI. Interestingly, atorvastatin is associated with cholestatic liver injury and simvastatin more with hepatocellular injury.

Acetaminophen-induced hepatotoxicity (dose-dependent)

Dose-dependent acetaminophen-induced hepatotoxicity should be suspected when a patient presents with serum aminotransferases in the thousands with only mild elevations in serum bilirubin. Liver injury typically becomes apparent 12 to 72 hours after ingestion and without treatment, liver failure follows in 72 to 96 hours. Within the United States, according to the ALF study group, acetaminophen accounted for 50% of all ALF cases.

Patients presenting with encephalopathy and/or kidney failure are at greatest risk of death and these patients require intensive care management and immediate referral to a liver transplant unit.

Management of patients with acetaminophen overdose involves two distinct objectives:

First. Remove all remaining pill fragments to reduce further absorption of drug. This is accomplished by gastric lavage, induction of emesis with ipecac syrup and administration of activated charcoal. This should be instituted in the first 12 to 24 hours to optimize efficacy.

Second. Consideration should be given to NAC therapy. The Rumack nomogram can be a helpful tool in deciding if a patient should be treated with NAC. This nomogram was designed to assess the patient's probability of developing hepatotoxicity from acetaminophen overdose. If the decision is made to start therapy, oral therapy should be tried if the patient can tolerate p.o. The initial loading dose is 140 mg/kg and then 70 mg/kg every 4 hours thereafter for a total of 72 hours or the INR is lower than 1.5. Alternatively, if the patient cannot tolerate p.o., the patient can be given intravenous NAC as a continuous infusion following the same parameters.

What's the evidence?

Chalasani, NP, Hayashi, PH, Bonjovsky, HL. " ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury". Am J Gastroenterol.. vol. 109. 2014. pp. 950-966.

(Recently published clinical guidelines by the ACG on the diagnosis and management of DILI)

Chalasani, N, Fontana, RJ, Bonkovsky, HL. " Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States". Gastroenterology. vol. 135. 2008. pp. 1924-1934.

(This study from the NIH-sponsored Drug-Induced Liver Injury Network (DILIN) reports on the prospective analysis of 300 patients within the United States who were diagnosed with DILI.)

Andrade, RJ, Lucena, MI, Fernandez, MC. " Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period". Gastroenterology. vol. 129. 2005. pp. 512-521.

(This work is another large prospective analysis of more than 400 DILI cases.)

Bjornsson, E, Jacobsen, EI, Kalaitzakis, E. "Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing". J Hepatol. 2011.

(The authors summarize a 12-year collection of adverse drug-related events from statin use in Sweden. They found that statins were associated with DILI at a rate of 1.2/100,000 users. One-third of the patients had jaundice and 3/73 (4%) either died from acute liver failure or had a liver transplant. Atorvastatin was the most commonly reported statin (41% of cases), and it was most commonly associated with a cholestatic or mixed pattern of liver enzyme elevations.)

Lammert, C, Einarsson, S, Saha, C. " Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals". Hepatology. vol. 47. 2008. pp. 2003-2009.

(This study found that the majority of DILI occurs at doses higher than 50 mg/day.)

Lammert, C, Bjornsson, E, Niklasson, A, Chalasani, N. "Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events". Hepatology. vol. 51. 2010. pp. 615-620.

(This study showed that oral medications with higher than 50% hepatic metabolism were at higher risk for DILI.)

Reuben, A, Koch, DG, Lee, WM. "Drug-induced acute liver failure: results of a U.S. multicenter, prospective study". Hepatology. vol. 52. 2010. pp. 2065-2076.

(This prospective U.S. registry of acute liver failure cases shows that 11% of all cases are due to idiosyncratic DILI, with the largest number of cases being attributable to antimicrobials.)

Lucena, MI, Andrade, RJ, Kaplowitz, N. " Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex". Hepatology. vol. 49. 2009. pp. 2001-2009.

(The authors used data from the prospective Spanish registry to show that cholestatic enzyme elevations were associated with advanced age [>60] and a male predominance, whereas younger age [<60] and female gender were associated with more hepatocellular enzyme elevations.)

Rochon, J, Protiva, P, Seeff, LB. " Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury". Hepatology. vol. 48. 2008. pp. 1175-1183.

(This study highlights the problems with reliability of the RUCAM for establishing a diagnosis of DILI.)

Bjornsson, E, Davidsdottir, L. "The long-term follow-up after idiosyncratic drug-induced liver injury and jaundice". J Hepatol. vol. 50. 2009. pp. 511-517.

(The authors show that with 10 years of follow-up after experiencingDILI, less than 4% of patients developed clinically significant liver disease.)

Lee, WM, Hynan, LS, Rossaro, L. " Intravenous N-acetylcysteine improves transplant-free survival in early stage nonacetaminophen acute liver failure". Gastroenterology. vol. 137. 2009. pp. 856-864.

(This study was a double-blind prospective trial that assessed the efficacy of N-acetylcysteine [NAC] in the treatment of nonacetaminophen acute liver failure. The results demonstrate that NAC improves transplant-free survival in certain patients.)
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